A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

Purpose: Lung cancers with epidermal growth factor receptor (EGFR)–activating mutations show good clinical response to gefitinib and erlotinib, selective tyrosine kinase inhibitors (TKI) to EGFR, but these tumors invariably develop drug resistance. Host stromal cells have been found to have a considerable effect on the behavior of cancer cells. Little is known, however, about the role of host cells on the sensitivity of cancer cells to receptor TKIs. We have therefore assessed the effect of crosstalk between stromal cells and lung cancer cells harboring EGFR mutations on susceptibility to EGFR-TKIs. Experimental Design: We evaluated the gefitinib sensitivity of lung cancer cells with EGFR-activating mutations, PC-9 and HCC827, when cocultured with fibroblasts and coinjected into severe combined immunodeficient mice. We also examined the effect of lung cancer cells to fibroblast recruitment. Results: Both human fibroblast cell lines and primary cultured fibroblasts produced various levels of hepatocyte growth factor (HGF). Lung cancer cells markedly recruited fibroblasts. The lung cancer cells became resistant to EGFR-TKIs when cocultured in vitro with HGF-producing fibroblasts and coinjected into severe combined immunodeficient mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4, successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Colocalization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens. Conclusions: These findings indicate that crosstalk to stromal fibroblasts plays a critical role in lung cancer resistance to EGFR-TKIs and may be an ideal therapeutic target in lung cancer with EGFR-activating mutations. (Clin Cancer Res 2009;15(21):6630–8)

The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.

BIM (BCL2L11) is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGF receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in EGFR-mutant forms of non–small cell lung cancer (NSCLC). Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug-resistant phenotype. Indeed, patients with NSCLC, who harbored this host BIM polymorphism, exhibited significantly inferior responses to EGFR-TKI treatment than individuals lacking this polymorphism. In an attempt to correct this response defect in the resistant group, we investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in EGFR-mutant NSCLC cell lines that also harbored the BIM polymorphism. Consistent with our clinical observations, we found that such cells were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells, which did not harbor the polymorphism. Notably, vorinostat increased expression in a dose-dependent manner of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKI–resistant cells. In xenograft models, while gefitinib induced marked regression via apoptosis of tumors without the BIM polymorphism, its combination with vorinostat was needed to induce marked regression of tumors with the BIM polymorphism in the same manner. Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR-mutant NSCLC where resistance to EGFR-TKI is associated with a common BIM polymorphism. Cancer Res; 73(8); 2428–34. ©2013 AACR.

Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents.